AXL Receptor in Breast Cancer: Molecular Involvement and Therapeutic Limitations

Falcone, Italia; Bazzichetto, Chiara; Bria, Emilio; Carbognin, Luisa; Malaguti, Paola; Ferretti, Gianluigi; Cognetti, F.; Milella, Michèle; Ciuffreda, Ludovica

doi:10.3390/ijms21228419

Cited by 20 publications

(18 citation statements)

References 124 publications

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“…In addition, AXL is involved in a variety of processes that promote tumor formation and metastasis, and is considered an effective biomarker for BC. Especially in triple negative (TN)BC tumors, AXL is considered a key factor in promoting EMT associated with mesenchymal and invasive phenotypes (13). In addition, we performed a pathway enrichment analysis and found that some of the mRNAs in BC are closely related to ribosomes (Figure 1D).…”

Section: Gene Function and Pathway Enrichment Analysesmentioning

confidence: 99%

A plasma-derived extracellular vesicle mRNA classifier for the detection of breast cancer

Cai¹,

Lin²,

Zhai³

et al. 2021

Gland Surg

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Background: According to the global cancer burden data released in 2020, breast cancer (BC) has become the most common cancer in the world. Similar to those of other cancers, the present methods used in clinic for diagnosing early BC are invasive, inaccurate, and insensitive. Hence, new non-invasive methods capable of early diagnosis are needed. Methods: We applied next-generation sequencing and analyzed the messenger RNA (mRNA) profiles of plasma extracellular vesicles (EVs) derived from 14 BC patients and 6 patients with benign breast lesions.We used 3 regression models, namely support vector machine (SVM), linear discriminate analysis (LDA), and logistic regression (LR), to develop classifiers for use in making predictive BC diagnoses; and used 259 plasma samples, including those obtained from 144 patients with BC, 72 patients with benign breast lesions, and 43 healthy women, which were divided into training groups and validation groups to verify their performances as classifiers by quantitative reverse transcription polymerase chain reaction (RT-qPCR). The area under the curve (AUC) and accuracy, sensitivity, and specificity of the classifiers were cross-validated with the leave-1-out cross-validation (LOOCV) method. Results: Among all combinations assessed with the 3 different regression models, an 8-mRNA combination, named EXOB mRNA , exhibited high performance [accuracy =71.9% and AUC =0.718, 95% confidence interval (CI): 0.652 to 0.784] in the training cohort after LOOCV was performed, showing the largest AUC in the SVM model. The mRNAs in EXOB mRNA were HLA-DRB1, HAVCR1, ENPEP, TIMP1, CD36, MARCKS, DAB2, and CXCL14. In the validation cohort, the AUC of EXOB mRNA was 0.737 (95% CI: 0.636 to 0.837). In addition, gene function and pathway analyses revealed that different levels of gene expression were associated with cancer. Conclusions: We developed a high-performing predictive classifiers including 8 mRNAs from plasma extracellular vesicles for diagnosing breast cancer.

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Section: Gene Function and Pathway Enrichment Analysesmentioning

confidence: 99%

A plasma-derived extracellular vesicle mRNA classifier for the detection of breast cancer

Cai¹,

Lin²,

Zhai³

et al. 2021

Gland Surg

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“…These kinases are generally present as monomers on the cell surface which bind with different growth factors to initiate kinase activities, auto-phosphorylation, and dimerization [ 26 , 27 ]. RTKs such as Met, Axl, Kit, and EGFR are altered in most cancers [ 28 , 29 ]. The proteins PDGFR, VEGFR, and fibroblast growth factor receptor (FGFR) are related to promote metastasis and angiogenesis under tumor microenvironment [ 30 ].…”

Section: Basic Concept On Targeting Receptor Tyrosine Kinases: Effective Strategies To Cure Cancermentioning

confidence: 99%

Emerging Importance of Tyrosine Kinase Inhibitors against Cancer: Quo Vadis to Cure?

Mongre

Mishra

Shukla

et al. 2021

IJMS

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GLOBOCAN 2020 estimated more than 19.3 million new cases, and about 10 million patients were deceased from cancer in 2020. Clinical manifestations showed that several growth factor receptors consisting of transmembrane and cytoplasmic tyrosine kinase (TK) domains play a vital role in cancer progression. Receptor tyrosine kinases (RTKs) are crucial intermediaries of the several cellular pathways and carcinogenesis that directly affect the prognosis and survival of higher tumor grade patients. Tyrosine kinase inhibitors (TKIs) are efficacious drugs for targeted therapy of various cancers. Therefore, RTKs have become a promising therapeutic target to cure cancer. A recent report shows that TKIs are vital mediators of signal transduction and cancer cell proliferation, angiogenesis, and apoptosis. In this review, we discuss the structure and function of RTKs to explore their prime role in cancer therapy. Various TKIs have been developed to date that contribute a lot to treating several types of cancer. These TKI based anticancer drug molecules are also discussed in detail, incorporating their therapeutic efficacy, mechanism of action, and side effects. Additionally, this article focuses on TKIs which are running in the clinical trial and pre-clinical studies. Further, to gain insight into the pathophysiological mechanism of TKIs, we also reviewed the impact of RTK resistance on TKI clinical drugs along with their mechanistic acquired resistance in different cancer types.

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“…Small molecular tyrosine kinase inhibitors and monoclonal antibodies (mAbs) are the main Axl inhibitors. A total of 26 small molecular kinase inhibitors against Axl have been reported to date, and have either been proven or are under clinical and preclinical development (4,5,15,16). However, most of these kinase inhibitors target several RTKs sharing similar kinase domains and, generally, Axl is not the primary target (2,4,15).…”

Section: Anti-axl Monoclonal Antibodies Attenuate the Migration Of Mda-mb-231 Breast Cancer Cellsmentioning

confidence: 99%

“…In total, only three kinase inhibitors have Axl as their selective target (5). R428 (BGB324) is the first selective kinase inhibitor to target Axl only and is currently undergoing phase II clinical trials (4,5,(16)(17)(18).…”

Section: Anti-axl Monoclonal Antibodies Attenuate the Migration Of Mda-mb-231 Breast Cancer Cellsmentioning

confidence: 99%

Anti‑Axl monoclonal antibodies attenuate the migration of MDA‑MB‑231 breast cancer cells

Chang

Li³

et al. 2021

Oncol Lett

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The receptor tyrosine kinase, anexelekto (Axl) is involved in tumor cell growth, migration and invasion, and has been associated with chemotherapy resistance, which makes it an attractive target for cancer therapy. In total, six Axl-targeted monoclonal antibodies (mAbs) and two antibody-drug conjugates have been reported in the last 10 years, which have been shown to have bioactivity in inhibiting tumor cell proliferation and migration. The Axl external cell domain (Axl -ECD ), consisting of 426 amino acids, has always been used as an antigen in the screening process for all six of these Axl-targeted mAbs. However, the Axl functional domain, which interacts with its natural ligand, growth arrest-specific protein 6 (Gas6), is only a small part of the Axl -ECD . Antibodies targeting the Axl functional domain may efficiently block Gas6-Axl binding and attenuate its downstream signals and activities. To the best of our knowledge, no mAbs targeting the Axl functional domain have been reported. In the present study, a major Axl functional domain interacting with Gas6 was determined using bioinformatics and structural biology methods. In MDA-MB-231 breast cancer cell assays, anti-Axl mAbs targeting this relatively specific Axl functional domain almost completely neutralized the stimulation of Gas6 in both Axl phosphorylation and cell migration assays, and showed similar activity to the positive control drug R428 (a small molecular tyrosine kinase inhibitor of Axl currently in phase II clinical trials) in the cell migration assay. Given the important role of Axl in tumor development and chemotherapy resistance, Axl-targeted mAbs could be used to inhibit tumor cells directly, as well as reduce the development of chemotherapy resistance by blocking Axl activity. The application of Axl-targeted mAbs combined with chemotherapy provides a promising treatment strategy for patients with tumors, particularly those with triple-negative breast cancer, for whom no targeted therapy is currently available.

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AXL Receptor in Breast Cancer: Molecular Involvement and Therapeutic Limitations

Cited by 20 publications

References 124 publications

A plasma-derived extracellular vesicle mRNA classifier for the detection of breast cancer

A plasma-derived extracellular vesicle mRNA classifier for the detection of breast cancer

Emerging Importance of Tyrosine Kinase Inhibitors against Cancer: Quo Vadis to Cure?

Anti‑Axl monoclonal antibodies attenuate the migration of MDA‑MB‑231 breast cancer cells

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